6-Sulfanilamidoindazole (6-SAI) is an orally administered anti-bacterial sulfonamide which induces arthritis and periarthritis in the ankles and hind paws of aged rats. The mechanisms responsible for induction of arthritis are unknown, however previous studies have shown that inflammation is independent of infectious agents, tissue crystal formation, mediators of acute inflammation and immediate and delayed type hypersensitivity reactions. These studies will be undertaken to determine the mechanisms of drug induced arithritis in rats and its possible relevance to arthritis in man. The working hypothesis in the proposal is that arthritis in 6-SAI treated rats is caused by at least two events which are: 1. the elevations in plasma fibrinogen concentration; 2. introduction of endotoxin or and endotoxin-like material from the gut which triggers microclot formation and the deposition of these clots in the ankles and paws where they initiate inflammation. To study this hypothesis six groups of experiments will be performed. The first experiment will be devoted to studying the effect of 6-SAI on fibrinogen synthesis in vitro. The second group of experiments is designed to evaluate the gastrointestinal flora in the pathogenesis of inflammation by use of germ free rats. The third set of experiments is designed to induce arthritis in hyperfibrinogenemic rats with endotoxin. The fourth group of experiments is designed to demonstrate fibronogen-fibrin material in pre-arthritic and arthritic joints. The fifth set of experiments was designed to suppress the arthritis by immunization with endotoxin or induction of hypofibrinogenemia. The last group of experiments is designed to determine whether stasis of blood by splinting would allow induction of arthritis in joints which are not affected in 6-SAI disease.